TY - JOUR
T1 - Leukemic stem cell quantification in newly diagnosed patients with chronic myeloid leukemia predicts response to nilotinib therapy
AU - Thielen, Noortje
AU - Richter, Johan
AU - Baldauf, Matthias
AU - Barbany, Gisela
AU - Fioretos, Thoas
AU - Giles, Francis
AU - Gjertsen, Bjørn Tore
AU - Hochhaus, Andreas
AU - Schuurhuis, Gerrit Jan
AU - Sopper, Sieghart
AU - Stenke, Leif
AU - Thunberg, Sarah
AU - Wolf, Dominik
AU - Ossenkoppele, Gert
AU - Porkka, Kimmo
AU - Janssen, Jeroen
AU - Mustjoki, Satu
N1 - Funding Information:
The authors thank the personnel at the participating stem cell laboratories at the VU University Medical Center, (Amsterdam, the Netherlands), Hematology Research Unit (Helsinki, Finland), Department of Clinical Genetics, Lund University (Lund, Sweden), and Department of Medicine, Karolinska University Hospital (Stockholm, Sweden) for their expert technical assistance. Novartis is acknowledged for financially supporting this study. The authors also thank patients, study nurses, and contributing investigators (listed below) for their participation in this trial
PY - 2016/8/15
Y1 - 2016/8/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-15-2791
DO - 10.1158/1078-0432.CCR-15-2791
M3 - Article
C2 - 27006491
AN - SCOPUS:84982170188
VL - 22
SP - 4030
EP - 4038
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 16
ER -