PMID- 27006491 OWN - NLM STAT- MEDLINE DCOM- 20180112 LR - 20220114 IS - 1557-3265 (Electronic) IS - 1078-0432 (Linking) VI - 22 IP - 16 DP - 2016 Aug 15 TI - Leukemic Stem Cell Quantification in Newly Diagnosed Patients With Chronic Myeloid Leukemia Predicts Response to Nilotinib Therapy. PG - 4030-8 LID - 10.1158/1078-0432.CCR-15-2791 [doi] 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. Clin Cancer Res; 22(16); 4030-8. (c)2016 AACR. CI - (c)2016 American Association for Cancer Research. FAU - Thielen, Noortje AU - Thielen N AD - Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. n.thielen@vumc.nl satu.mustjoki@helsinki.fi. FAU - Richter, Johan AU - Richter J AD - Department of Hematology and Vascular Disorders, Skane University Hospital, Lund, Sweden. FAU - Baldauf, Matthias AU - Baldauf M AD - Division for Bioinformatics, Medical University of Innsbruck and Oncotyrol GmbH, Center for Personalized Cancer Medicine, Innsbruck, Austria. FAU - Barbany, Gisela AU - Barbany G AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. FAU - Fioretos, Thoas AU - Fioretos T AD - Department of Clinical Genetics, Lund University, Lund, Sweden. FAU - Giles, Francis AU - Giles F AD - NMDTI, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. FAU - Gjertsen, Bjorn-Tore AU - Gjertsen BT AD - Department of Hematology, University of Bergen, Bergen, Norway. FAU - Hochhaus, Andreas AU - Hochhaus A AD - Hematology/Oncology, Universitatsklinikum Jena, Jena, Germany. FAU - Schuurhuis, Gerrit Jan AU - Schuurhuis GJ AD - Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. FAU - Sopper, Sieghart AU - Sopper S AD - Department of Hematology and Oncology, Innsbruck Medical University and Tyrolean Cancer Research Institute, Innsbruck, Austria. FAU - Stenke, Leif AU - Stenke L AD - Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden. FAU - Thunberg, Sarah AU - Thunberg S AD - Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden. FAU - Wolf, Dominik AU - Wolf D AD - Medical Clinic 3, Oncology, Hematology and Rheumatology, University Clinic Bonn (UKB), Bonn, Germany. FAU - Ossenkoppele, Gert AU - Ossenkoppele G AD - Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. FAU - Porkka, Kimmo AU - Porkka K AD - Hematology Research Unit Helsinki, University of Helsinki and Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland. FAU - Janssen, Jeroen AU - Janssen J AD - Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands. FAU - Mustjoki, Satu AU - Mustjoki S AD - 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. LA - eng SI - ClinicalTrials.gov/NCT01061177 PT - Journal Article DEP - 20160322 PL - United States TA - Clin Cancer Res JT - Clinical cancer research : an official journal of the American Association for Cancer Research JID - 9502500 RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - F41401512X (nilotinib) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/administration & dosage/adverse effects/*therapeutic use MH - Biomarkers MH - Cell Count MH - Clinical Trials, Phase III as Topic MH - Female MH - Humans MH - Immunophenotyping MH - In Situ Hybridization, Fluorescence MH - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*diagnosis/*drug therapy MH - Male MH - Middle Aged MH - Multicenter Studies as Topic MH - Neoplastic Stem Cells/*pathology MH - Protein Kinase Inhibitors/administration & dosage/adverse effects/*therapeutic use MH - Pyrimidines/administration & dosage/adverse effects/*therapeutic use MH - Treatment Outcome MH - Young Adult EDAT- 2016/03/24 06:00 MHDA- 2018/01/13 06:00 CRDT- 2016/03/24 06:00 PHST- 2015/12/08 00:00 [received] PHST- 2016/03/06 00:00 [accepted] PHST- 2016/03/24 06:00 [entrez] PHST- 2016/03/24 06:00 [pubmed] PHST- 2018/01/13 06:00 [medline] AID - 1078-0432.CCR-15-2791 [pii] AID - 10.1158/1078-0432.CCR-15-2791 [doi] PST - ppublish SO - Clin Cancer Res. 2016 Aug 15;22(16):4030-8. doi: 10.1158/1078-0432.CCR-15-2791. Epub 2016 Mar 22.