Frontiers in Oncology (May 2018)
Residual Peripheral Blood CD26+ Leukemic Stem Cells in Chronic Myeloid Leukemia Patients During TKI Therapy and During Treatment-Free Remission
- Monica Bocchia,
- Anna Sicuranza,
- Elisabetta Abruzzese,
- Alessandra Iurlo,
- Santina Sirianni,
- Antonella Gozzini,
- Sara Galimberti,
- Lara Aprile,
- Bruno Martino,
- Patrizia Pregno,
- Federica Sorà,
- Giulia Alunni,
- Carmen Fava,
- Fausto Castagnetti,
- Luca Puccetti,
- Massimo Breccia,
- Daniele Cattaneo,
- Marzia Defina,
- Olga Mulas,
- Claudia Baratè,
- Giovanni Caocci,
- Simona Sica,
- Alessandro Gozzetti,
- Luigiana Luciano,
- Monica Crugnola,
- Mario Annunziata,
- Mario Tiribelli,
- Paola Pacelli,
- Ilaria Ferrigno,
- Ilaria Ferrigno,
- Emilio Usala,
- Nicola Sgherza,
- Gianantonio Rosti,
- Alberto Bosi,
- Donatella Raspadori
Affiliations
- Monica Bocchia
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Anna Sicuranza
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Elisabetta Abruzzese
- Department of Hematology, Tor Vergata University Hospital, Rome, Italy
- Alessandra Iurlo
- IRCCS Ca’ Granda – Maggiore Policlinico Hospital Foundation, Milan, Italy
- Santina Sirianni
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Antonella Gozzini
- Department of Hematology, University of Firenze, Florence, Italy
- Sara Galimberti
- Department of Hematology, Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Lara Aprile
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Bruno Martino
- Hematology Unit Bianchi Melacrino Morelli Hospital, Reggio Calabria, Italy
- Patrizia Pregno
- Hematology Division, Azienda Ospedaliera Città della Salute e della Scienza, Torino, Italy
- Federica Sorà
- Fondazione Policlinico Universitario A Gemelli IRCSS Università Cattolica Sacro Cuore, Rome, Italy
- Giulia Alunni
- Azienda Ospedaliera S. Maria, Terni, Italy
- Carmen Fava
- 0Hematology Division, Ospedale Mauriziano, Torino, Italy
- Fausto Castagnetti
- 1Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology and Medical Oncology “L. & A. Seràgnoli”, University of Bologna, Bologna, Italy
- Luca Puccetti
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Massimo Breccia
- 2Hematology, Biotecnologie Cellulari ed Ematologia, University “La Sapienza”, Rome, Italy
- Daniele Cattaneo
- IRCCS Ca’ Granda – Maggiore Policlinico Hospital Foundation, Milan, Italy
- Marzia Defina
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Olga Mulas
- 3Hematology Unit, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
- Claudia Baratè
- Department of Hematology, Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Giovanni Caocci
- 3Hematology Unit, Department of Medical Sciences, University of Cagliari, Cagliari, Italy
- Simona Sica
- Fondazione Policlinico Universitario A Gemelli IRCSS Università Cattolica Sacro Cuore, Rome, Italy
- Alessandro Gozzetti
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Luigiana Luciano
- 4Hematology Federico II University, Naples, Italy
- Monica Crugnola
- 5Hematology Unit, Maggiore Hospital University of Parma, Parma, Italy
- Mario Annunziata
- 6Hematology, Cardarelli Hospital, Naples, Italy
- Mario Tiribelli
- 7Division of Hematology and BMT, Department of Medical and Morphological Researches, University of Udine, Udine, Italy
- Paola Pacelli
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Ilaria Ferrigno
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- Ilaria Ferrigno
- 8Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Emilio Usala
- 9Hematology Unit, Ospedale Oncologico A. Businco, Cagliari, Italy
- Nicola Sgherza
- 0Hematology Unit, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy
- Gianantonio Rosti
- 1Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology and Medical Oncology “L. & A. Seràgnoli”, University of Bologna, Bologna, Italy
- Alberto Bosi
- Department of Hematology, University of Firenze, Florence, Italy
- Donatella Raspadori
- Hematology Unit, Department of Medicine, Surgery and Neuroscience, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena, Italy
- DOI
- https://doi.org/10.3389/fonc.2018.00194
- Journal volume & issue
-
Vol. 8
Abstract
Chronic myeloid leukemia (CML) patients in sustained “deep molecular response” may stop TKI treatment without disease recurrence; however, half of them lose molecular response shortly after TKI withdrawing. Well-defined eligibility criteria to predict a safe discontinuation up-front are still missing. Relapse is probably due to residual quiescent TKI-resistant leukemic stem cells (LSCs) supposedly transcriptionally low/silent and not easily detectable by BCR-ABL1 qRT-PCR. Bone marrow Ph+ CML CD34+/CD38− LSCs were found to specifically co-express CD26 (dipeptidylpeptidase-IV). We explored feasibility of detecting and quantifying CD26+ LSCs by flow cytometry in peripheral blood (PB). Over 400 CML patients (at diagnosis and during/after therapy) entered this cross-sectional study in which CD26 expression was evaluated by a standardized multiparametric flow cytometry analysis on PB CD45+/CD34+/CD38− stem cell population. All 120 CP-CML patients at diagnosis showed measurable PB CD26+ LSCs (median 19.20/μL, range 0.27–698.6). PB CD26+ LSCs were also detectable in 169/236 (71.6%) CP-CML patients in first-line TKI treatment (median 0.014 cells/μL; range 0.0012–0.66) and in 74/112 (66%), additional patients studied on treatment-free remission (TFR) (median 0.015/μL; range 0.006–0.76). Notably, no correlation between BCR-ABL/ABLIS ratio and number of residual LSCs was found both in patients on or off TKIs. This is the first evidence that “circulating” CML LSCs persist in the majority of CML patients in molecular response while on TKI treatment and even after TKI discontinuation. Prospective studies evaluating the dynamics of PB CD26+ LSCs during TKI treatment and the role of a “stem cell response” threshold to achieve and maintain TFR are ongoing.
Keywords
