{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T16:13:57Z","timestamp":1770912837542,"version":"3.50.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T00:00:00Z","timestamp":1685059200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la Ricerca Sul Cancro ETS","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+\/CD38-\/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> CML LSCs could be easily identified by flow-cytometry as they express the CD34+\/CD38-\/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> After a median observation time of 33\u00a0months from TKI discontinuation, 38\/109 (35%) patients failed TFR after a median time of 4\u00a0months, while 71\/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48\/109 (44%) patients and detectable in 61\/109 (56%). No statistically significant correlation between detectable\/undetectable CD26+LSCs and the rate of TFR loss was found (<jats:italic>p<\/jats:italic> = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib (<jats:italic>p<\/jats:italic> = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss.<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of \u201cfluctuating\u201d values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs \u201cburden\u201d playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs\u2019 ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing.<\/jats:p>","DOI":"10.3389\/fphar.2023.1194712","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T04:23:31Z","timestamp":1685075011000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Prospective monitoring of chronic myeloid leukemia patients from the time of TKI discontinuation: the fate of peripheral blood CD26+ leukemia stem cells"],"prefix":"10.3389","volume":"14","author":[{"given":"Paola","family":"Pacelli","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adele","family":"Santoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Sicuranza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Abruzzese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Giai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Crugnola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Annunziata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Galimberti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Iurlo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigiana","family":"Luciano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Sor\u00e0","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmen","family":"Fava","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Bestoso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Marzano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Cartocci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marzia","family":"Defina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Sammartano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Cencini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donatella","family":"Raspadori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Bocchia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1007\/s11899-021-00653-1","article-title":"Treatment-free remission: The new goal in CML therapy","volume":"16","author":"Atallah","year":"2021","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4280","DOI":"10.1182\/bloodadvances.2019000865","article-title":"Managing chronic myeloid leukemia for treatment-free remission: A proposal from the GIMEMA CML WP","volume":"23","author":"Baccarani","year":"2019","journal-title":"Blood Adv."},{"key":"B3","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1038\/s41375-018-0252-4","article-title":"Targeting quiescent leukemic stem cells using second generation autophagy inhibitors","volume":"33","author":"Baquero","year":"2019","journal-title":"Leukemia"},{"key":"B4","doi-asserted-by":"publisher","first-page":"194","DOI":"10.3389\/fonc.2018.00194","article-title":"Residual peripheral blood CD26+ leukemic stem cells in chronic myeloid leukemia patients during TKI therapy and during treatment-free remission","volume":"30","author":"Bocchia","year":"2018","journal-title":"Front. Oncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2851","DOI":"10.1200\/JCO.2015.66.2866","article-title":"Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population","volume":"34","author":"Bower","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1080\/17474086.2021.1852924","article-title":"Tyrosine kinase inhibitor discontinuation in the management of chronic myeloid leukemia: A critical review of the current practice","volume":"13","author":"Breccia","year":"2020","journal-title":"Expert Rev. Hematol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3567","DOI":"10.1016\/j.molimm.2008.05.014","article-title":"Interaction of human PD-L1 and B7-1","volume":"45","author":"Butte","year":"2008","journal-title":"Mol. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1016\/j.exphem.2015.08.004","article-title":"Killer immunoglobulin-like receptors can predict TKI treatment-free remission in chronic myeloid leukemia patients","volume":"43","author":"Caocci","year":"2015","journal-title":"Exp. Hematol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1007\/s11523-021-00831-4","article-title":"Making treatment-free remission (TFR) easier in chronic myeloid leukemia: Fact-checking and practical management tools","volume":"16","author":"Castagnetti","year":"2021","journal-title":"Target Oncol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s40259-017-0225-6","article-title":"Chronic myeloid leukemia: Immunobiology and novel immunotherapeutic approaches","volume":"31","author":"Cayssials","year":"2017","journal-title":"BioDrugs"},{"key":"B11","doi-asserted-by":"publisher","first-page":"711","DOI":"10.2174\/15680096113139990085","article-title":"New insights into biology of chronic myeloid leukemia: Implications in therapy","volume":"13","author":"Cea","year":"2013","journal-title":"Curr. Cancer Drug Targets"},{"key":"B12","doi-asserted-by":"publisher","first-page":"841546","DOI":"10.3389\/fonc.2022.841546","article-title":"Impact of BCR-ABL1 transcript type on outcome in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: A pairwise and bayesian Network meta-analysis","volume":"12","author":"Chen","year":"2022","journal-title":"Front. Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"769730","DOI":"10.3389\/fonc.2021.769730","article-title":"Treatment-free remission in chronic myeloid leukemia and new approaches by targeting leukemia stem cells","volume":"28","author":"Chen","year":"2021","journal-title":"Front. Oncol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e55818","DOI":"10.1371\/journal.pone.0055818","article-title":"Increased level of myeloid-derived suppressor cells, programmed death receptor ligand 1\/programmed death receptor 1, and soluble CD25 in Sokal high risk chronic myeloid leukemia","volume":"8","author":"Christiansson","year":"2013","journal-title":"PLoS One"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e297","DOI":"10.3324\/haematol.2017.168740","article-title":"E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy","volume":"102","author":"Claudiani","year":"2017","journal-title":"Haematologica"},{"key":"B16","doi-asserted-by":"publisher","first-page":"4554","DOI":"10.1182\/blood-2011-04-347575","article-title":"Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population","volume":"118","author":"Efficace","year":"2011","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.3324\/haematol.2018.205054","article-title":"Observational study of chronic myeloid leukemia Italian patients who discontinued tyrosine kinase inhibitors in clinical practice","volume":"104","author":"Fava","year":"2019","journal-title":"Haematologica"},{"key":"B18","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1007\/s10147-018-1368-2","article-title":"Feasibility of the imatinib stop study in the Japanese clinical setting: Delightedly overcome CML expert stop TKI trial (DOMEST trial)","volume":"24","author":"Fujisawa","year":"2019","journal-title":"Int. J. Clin. Oncol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"555","DOI":"10.3389\/fonc.2018.00555","article-title":"The polycomb BMI1 protein is Co-expressed with CD26+ in leukemic stem cells of chronic myeloid leukemia","volume":"6","author":"Galimberti","year":"2018","journal-title":"Front. Oncol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1093\/jnci\/djr060","article-title":"Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib","volume":"103","author":"Gambacorti-Passerini","year":"2011","journal-title":"J. Natl. Cancer Inst."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2317","DOI":"10.1185\/03007995.2014.944973","article-title":"Impact of low-grade adverse events on health-related quality of life in adult patients receiving imatinib or nilotinib for newly diagnosed Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase","volume":"30","author":"Gu\u00e9rin","year":"2014","journal-title":"Curr. Med. Res. Opin."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2398","DOI":"10.1038\/leu.2017.253","article-title":"Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants","volume":"31","author":"Hehlmann","year":"2017","journal-title":"Leukemia"},{"key":"B23","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1038\/s41375-020-0776-2","article-title":"European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia","volume":"34","author":"Hochhaus","year":"2020","journal-title":"Leukemia"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1038\/s41375-021-01238-w","article-title":"Improving outcomes in chronic myeloid leukemia through harnessing the immunological landscape","volume":"35","author":"Hsieh","year":"2021","journal-title":"Leukemia"},{"key":"B25","doi-asserted-by":"publisher","first-page":"469","DOI":"10.3389\/fimmu.2017.00469","article-title":"Immune effector recovery in chronic myeloid leukemia and treatment-free remission","volume":"24","author":"Hughes","year":"2017","journal-title":"Front. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1038\/leu.2016.360","article-title":"Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia","volume":"31","author":"Ilander","year":"2017","journal-title":"Leukemia"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1002\/ajh.26556","article-title":"Tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia: Eligibility criteria and predictors of success","volume":"97","author":"Inzoli","year":"2022","journal-title":"Am. J. Hematol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1111\/bjh.16718","article-title":"Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells","volume":"191","author":"Irani","year":"2020","journal-title":"Br. J. Haematol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"839915","DOI":"10.3389\/fonc.2022.839915","article-title":"Treatment-free remission in chronic myeloid leukemia patients treated with low-dose TKIs: A feasible option also in the real-life. A campus CML study","volume":"12","author":"Iurlo","year":"2022","journal-title":"Front. Oncol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1016\/S1470-2045(10)70233-3","article-title":"Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre stop imatinib (STIM) trial","volume":"11","author":"Mahon","year":"2010","journal-title":"Lancet Oncol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/nrc2147","article-title":"Chronic myeloid leukaemia as a model of disease evolution in human cancer","volume":"7","author":"Melo","year":"2007","journal-title":"Cancer"},{"key":"B32","doi-asserted-by":"publisher","first-page":"117","DOI":"10.3390\/cells10010117","article-title":"Chronic myeloid leukemia: A model disease of the past, present and future","volume":"10","author":"Minciacchi","year":"2021","journal-title":"Cells"},{"key":"B33","doi-asserted-by":"publisher","first-page":"8950","DOI":"10.4081\/hr.2020.8950","article-title":"Treatment free remission in chronic myeloid leukemia: Lights and shadows","volume":"12","author":"Molica","year":"2020","journal-title":"Hematol. Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1528","DOI":"10.1182\/blood-2008-09-179697","article-title":"Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression","volume":"114","author":"Mumprecht","year":"2009","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","first-page":"12171","DOI":"10.1182\/blood-2022-169085","article-title":"In search of drivers of cd34+\/CD38-\/cd26+ leukemia stem cells persistence in CML patients","volume":"140","author":"Pacelli","year":"2022","journal-title":"Blood"},{"key":"B36","doi-asserted-by":"publisher","first-page":"4855","DOI":"10.1182\/bloodadvances.2020003235","article-title":"Treatment-free remission in patients with chronic myeloid leukemia: Recommendations of the LALNET expert panel","volume":"5","author":"Pavlovsky","year":"2021","journal-title":"Blood Adv."},{"key":"B37","doi-asserted-by":"publisher","first-page":"5594","DOI":"10.3390\/jcm11195594","article-title":"Immunomodulatory effects of IFN\u03b1 on T and NK cells in chronic myeloid leukemia patients in deep molecular response preparing for treatment discontinuation","volume":"11","author":"Puzzolo","year":"2022","journal-title":"J. Clin. Med."},{"key":"B38","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1002\/cyto.b.21764","article-title":"Flow cytometry assessment of CD26+ leukemic stem cells in peripheral blood: A simple and rapid new diagnostic tool for chronic myeloid leukemia","volume":"96","author":"Raspadori","year":"2019","journal-title":"Cytom. B Clin. Cytom."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2416","DOI":"10.1038\/s41375-021-01173-w","article-title":"Molecular status 36 months after TKI discontinuation in CML is highly predictive for subsequent loss of MMR-final report from AFTER-SKI","volume":"35","author":"Richter","year":"2021","journal-title":"Leukemia"},{"key":"B40","doi-asserted-by":"publisher","first-page":"4175","DOI":"10.3390\/cancers13164175","article-title":"Treatment-free remission in chronic myeloid leukemia: Can we identify prognostic factors?","volume":"13","author":"Saifullah","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1016\/S1470-2045(18)30192-X","article-title":"Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): A prespecified interim analysis of a prospective, multicentre, non-randomised, trial","volume":"19","author":"Saussele","year":"2018","journal-title":"Lancet Oncol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1517\/14712598.2015.1051028","article-title":"Programmed death-1 checkpoint blockade in acute myeloid leukemia","volume":"15","author":"Sehgal","year":"2015","journal-title":"Expert Opin. Biol. Ther."},{"key":"B43","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/978-3-319-97746-1_6","article-title":"Preservation of quiescent chronic myelogenous leukemia stem cells by the bone marrow microenvironment","volume":"1100","author":"Shah","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1080\/10428194.2019.1675879","article-title":"Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: The DASFREE study","volume":"61","author":"Shah","year":"2020","journal-title":"Leuk. Lymphoma"},{"key":"B45","doi-asserted-by":"publisher","first-page":"891","DOI":"10.3390\/cancers14040891","article-title":"CD26\/DPP-4 in chronic myeloid leukemia","volume":"14","author":"Sicuranza","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B46","doi-asserted-by":"publisher","first-page":"381","DOI":"10.11406\/rinketsu.58.381","article-title":"Chronic myeloid leukemia and NK cell immunity","volume":"58","author":"Ureshino","year":"2017","journal-title":"Rinsho Ketsueki"},{"key":"B47","doi-asserted-by":"publisher","first-page":"E184","DOI":"10.1002\/ajh.23804","article-title":"First-line treatment of 102 chronic myeloid leukemia patients with imatinib: A long-term single institution analysis","volume":"89","author":"Vigan\u00f2","year":"2014","journal-title":"Am. J. Hematol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1182\/blood-2013-01-477687","article-title":"Measuring the symptom burden associated with the treatment of chronic myeloid leukemia","volume":"122","author":"Williams","year":"2013","journal-title":"Blood"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1194712\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T04:23:36Z","timestamp":1685075016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1194712\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,26]]},"references-count":48,"alternative-id":["10.3389\/fphar.2023.1194712"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1194712","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,26]]},"article-number":"1194712"}}