title: Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients.
abstract: Chronic myeloid leukemia (CML) stem cells appear resistant to tyrosine kinase inhibitors (TKIs) in vitro, but their impact and drug sensitivity in vivo has not been systematically assessed. We prospectively analyzed the proportion of Philadelphia chromosome-positive leukemic stem cells (LSCs, Ph+CD34+CD38-) and progenitor cells (LPCs, Ph+CD34+CD38+) from 46 newly diagnosed CML patients both at the diagnosis and during imatinib or dasatinib therapy (ClinicalTrials.gov NCT00852566). At diagnosis, the proportion of LSCs varied markedly (1-100%) between individual patients with a significantly lower median value as compared with LPCs (79% vs 96%, respectively, P=0.0001). The LSC burden correlated with leukocyte count, spleen size, hemoglobin and blast percentage. A low initial LSC percentage was associated with less therapy-related hematological toxicity and superior cytogenetic and molecular responses. After initiation of TKI therapy, the LPCs and LSCs rapidly decreased in both therapy groups, but at 3 months time point the median LPC level was significantly lower in dasatinib group compared with imatinib patients (0.05% vs 0.68%, P=0.032). These data detail for the first time the prognostic significance of the LSC burden at diagnosis and show that in contrast to in vitro data, TKI therapy rapidly eradicates the majority of LSCs in patients.
authors: Hematology Research Unit Helsinki, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. satu.mustjoki@helsinki.fi
authors: S
authors: S
authors: Mustjoki
authors: J
authors: J
authors: Richter
authors: G
authors: G
authors: Barbany
authors: H
authors: H
authors: Ehrencrona
authors: T
authors: T
authors: Fioretos
authors: T
authors: T
authors: Gedde-Dahl
authors: B T
authors: BT
authors: Gjertsen
authors: R
authors: R
authors: Hovland
authors: S
authors: S
authors: Hernesniemi
authors: D
authors: D
authors: Josefsen
authors: P
authors: P
authors: Koskenvesa
authors: I
authors: I
authors: Dybedal
authors: B
authors: B
authors: Markevärn
authors: T
authors: T
authors: Olofsson
authors: U
authors: U
authors: Olsson-Strömberg
authors: K
authors: K
authors: Rapakko
authors: S
authors: S
authors: Thunberg
authors: L
authors: L
authors: Stenke
authors: B
authors: B
authors: Simonsson
authors: K
authors: K
authors: Porkka
authors: H
authors: H
authors: Hjorth-Hansen
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use*; D000069439:Dasatinib; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010865:Pilot Projects; D010879:Piperazines / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D000069439:Dasatinib