title: Leukemic Stem Cell Quantification in Newly Diagnosed Patients With Chronic Myeloid Leukemia Predicts Response to Nilotinib Therapy.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. n.thielen@vumc.nl satu.mustjoki@helsinki.fi.
authors.forename: Noortje
authors.initials: N
authors.lastname: Thielen
authors.affiliation: Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Richter
authors.affiliation: Division for Bioinformatics, Medical University of Innsbruck and Oncotyrol GmbH, Center for Personalized Cancer Medicine, Innsbruck, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Baldauf
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gisela
authors.initials: G
authors.lastname: Barbany
authors.affiliation: Department of Clinical Genetics, Lund University, Lund, Sweden.
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
authors.affiliation: NMDTI, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.affiliation: Department of Hematology, University of Bergen, Bergen, Norway.
authors.forename: Bjørn-Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: Hematology/Oncology, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Schuurhuis
authors.affiliation: Department of Hematology and Oncology, Innsbruck Medical University and Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: Sieghart
authors.initials: S
authors.lastname: Sopper
authors.affiliation: Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Stenke
authors.affiliation: Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Sarah
authors.initials: S
authors.lastname: Thunberg
authors.affiliation: Medical Clinic 3, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Ossenkoppele
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Janssen
authors.affiliation: Hematology Research Unit Helsinki, University of Helsinki and Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland. Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland. n.thielen@vumc.nl satu.mustjoki@helsinki.fi.
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D002452:Cell Count; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D014411:Neoplastic Stem Cells / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C498826:nilotinib