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.

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MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

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