TY - JOUR
T1 - Residual peripheral blood CD26+ leukemic stem cells in chronic myeloid leukemia patients during TKI therapy and during treatment-free remission
AU - Bocchia, Monica
AU - Sicuranza, Anna
AU - Abruzzese, Elisabetta
AU - Iurlo, Alessandra
AU - Sirianni, Santina
AU - Gozzini, Antonella
AU - Galimberti, Sara
AU - Aprile, Lara
AU - Martino, Bruno
AU - Pregno, Patrizia
AU - Sorà, Federica
AU - Alunni, Giulia
AU - Fava, Carmen
AU - Castagnetti, Fausto
AU - Puccetti, Luca
AU - Breccia, Massimo
AU - Cattaneo, Daniele
AU - Defina, Marzia
AU - Mulas, Olga
AU - Baratè, Claudia
AU - Caocci, Giovanni
AU - Sica, Simona
AU - Gozzetti, Alessandro
AU - Luciano, Luigiana
AU - Crugnola, Monica
AU - Annunziata, Mario
AU - Tiribelli, Mario
AU - Pacelli, Paola
AU - Ferrigno, Ilaria
AU - Usala, Emilio
AU - Sgherza, Nicola
AU - Rosti, Gianantonio
AU - Bosi, Alberto
AU - Raspadori, Donatella
PY - 2018/5/30
Y1 - 2018/5/30
N2 - 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 offTKIs. 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.
AB - 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 offTKIs. 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.
KW - CD26
KW - Chronic myeloid leukemia
KW - Flow cytometry
KW - Leukemic stem cells
KW - Minimal residual disease
KW - TKI
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UR - http://www.scopus.com/inward/citedby.url?scp=85047827251&partnerID=8YFLogxK
U2 - 10.3389/fonc.2018.00194
DO - 10.3389/fonc.2018.00194
M3 - Article
AN - SCOPUS:85047827251
VL - 8
JO - Frontiers in Oncology
JF - Frontiers in Oncology
SN - 2234-943X
IS - MAY
M1 - 194
ER -