Clinical cancer research : an official journal of the American Association for Cancer Research · 2016
Leukemic Stem Cell Quantification in Newly Diagnosed Patients With Chronic Myeloid Leukemia Predicts Response to Nilotinib Therapy.
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Thielen Noortje, Richter Johan, Baldauf Matthias, Barbany Gisela, Fioretos Thoas, Giles Francis, Gjertsen Bjørn-Tore, Hochhaus Andreas, Schuurhuis Gerrit Jan, Sopper Sieghart, Stenke Leif, Thunberg Sarah, Wolf Dominik, Ossenkoppele Gert, Porkka Kimmo, Janssen Jeroen, Mustjoki Satu
Аннотация
PURPOSE: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myelogenous leukemia (CML). We identified Philadelphia chromosome (Ph)-positive CD34(+)CD38(-) bone marrow cells (here denoted LSCs) and addressed their response-predictive value in patients with CML (n = 48) subjected to nilotinib in the ENEST1st trial (NCT01061177).
EXPERIMENTAL DESIGN: Two flow cytometry-based cell sorting methods were used with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively.
RESULTS: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, and hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC and FISH), 6 (MPFC), 9 (FISH), and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34(+)CD38(-) cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions.
CONCLUSIONS: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in patients with CML subjected to first-line nilotinib therapy. Clin Cancer Res; 22(16); 4030-8. ©2016 AACR.
EXPERIMENTAL DESIGN: Two flow cytometry-based cell sorting methods were used with multiparameter-directed CD45- (MPFC) and BCR-ABL1 probe-linked (FISH) identification of Ph-positive cells, respectively.
RESULTS: We observed a positive correlation between the proportion of LSCs at diagnosis and established prognostic markers (blast count, spleen size, Sokal score, and hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC and FISH), 6 (MPFC), 9 (FISH), and 15 months (FISH). During nilotinib therapy, the proportion of LSCs decreased rapidly. At 3 months, a median of only 0.3% LSCs remained among CD34(+)CD38(-) cells, and in 33% of the patients the LSC clone was not detectable anymore (FISH). The response kinetics was similar in LSC fractions as it was in the progenitor and unseparated bone marrow cell fractions.
CONCLUSIONS: The proportion of LSCs at diagnosis, as analyzed by two independent methodologies, reflects the biology of the disease and appeared as a prognostic and response-predictive marker in patients with CML subjected to first-line nilotinib therapy. Clin Cancer Res; 22(16); 4030-8. ©2016 AACR.
Предметные рубрики MeSH
AdultAgedAged, 80 and overAntineoplastic AgentsBiomarkersCell CountClinical Trials, Phase III as TopicFemaleHumansImmunophenotypingIn Situ Hybridization, FluorescenceLeukemia, Myelogenous, Chronic, BCR-ABL PositiveMaleMiddle AgedMulticenter Studies as TopicNeoplastic Stem CellsProtein Kinase InhibitorsPyrimidinesTreatment OutcomeYoung Adult