Leukemic stem cell quantification in newly diagnosed chronic myeloid leukemia patients predicts response to nilotinib therapy

PURPOSE: Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myeloid leukemia (CML). We identified Philadelphia chromosome (Ph) positive CD34+CD38- bone marrow cells (here denoted LSCs) and addressed their response-predictive value in CML patients (n=48) subjected to nilotinib in the ENEST1st trial (NCT01061177).EXPERIMENTAL DESIGN: Two flow cytometry-based cell sorting methods were employed 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, hemoglobin). Conversely, a high LSC burden predicted for an inferior molecular response at 3 (MPFC, 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.CONCLUSION: 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 CML patients subjected to first-line nilotinib therapy.

Richter, JohanLund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Skåne University Hospital(Swepub:lu)med-jri (author)
Baldauf, MatthiasMedical University of Innsbruck (author)
Barbany, GiselaKarolinska Institute (author)
Fioretos, ThoasLund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine(Swepub:lu)kgen-tfi (author)
Giles, FrancisNorthwestern University (author)
Gjertsen, Bjørn ToreUniversity of Bergen (author)
Hochhaus, AndreasUniversitätsklinikum Jena (author)
Schuurhuis, Gerrit JanAmsterdam UMC - Vrije Universiteit Amsterdam (author)
Sopper, SieghartMedical University of Innsbruck (author)
Stenke, LeifKarolinska University Hospital (author)
Thunberg, SarahKarolinska University Hospital (author)
Wolf, DominikUniversity Hospital Bonn (author)
Ossenkoppele, GertAmsterdam UMC - Vrije Universiteit Amsterdam (author)
Porkka, KimmoUniversity of Helsinki (author)
Janssen, JeroenAmsterdam UMC - Vrije Universiteit Amsterdam (author)
Mustjoki, SatuUniversity of Helsinki (author)
Amsterdam UMC - Vrije Universiteit AmsterdamAvdelningen för molekylärmedicin och genterapi (creator_code:org_t)

By the author/editor: Thielen, Noortje; Richter, Johan; Baldauf, Matthia ...; Barbany, Gisela; Fioretos, Thoas; Giles, Francis; show more...; Gjertsen, Bjørn ...; Hochhaus, Andrea ...; Schuurhuis, Gerr ...; Sopper, Sieghart; Stenke, Leif; Thunberg, Sarah; Wolf, Dominik; Ossenkoppele, Ge ...; Porkka, Kimmo; Janssen, Jeroen; Mustjoki, Satu; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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