Abstract
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). 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. 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. 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.
Highlights
The introduction of the tyrosine kinase inhibitor (TKI) imatinib and, more recently, of the second-generation TKIs nilotinib, dasatinib, and bosutinib marked a revolution in the treatment of patients with chronic myelogenous leukemia (CML)
Patients with high Sokal or Euro scores, based on hematologic parameters, spleen size and age, and those with slow reduction of BCR-ABL1 transcripts in response to starting treatment are at increased risk of treatment failure [11,12,13].our study groups have previously demonstrated that the composition of the CD34þCD38À stem cell compartment at diagnosis, as assessed by multiparameter flow cytometry (MPFC) or stem and progenitor cell sorting followed by FISH, predicts for later response, and for hematologic toxicity during TKI treatment [14, 15]
We found that the proportion of leukemic stem cells (LSCs) at diagnosis, as analyzed by two independent methodologies [multiparameter flow cytometry (MPFC) and sorting plus FISH], reflects the biology of the disease and appeared as a response-predictive marker in CML
Summary
The introduction of the tyrosine kinase inhibitor (TKI) imatinib and, more recently, of the second-generation TKIs nilotinib, dasatinib, and bosutinib marked a revolution in the treatment of patients with chronic myelogenous leukemia (CML). Patients with high Sokal or Euro scores, based on hematologic parameters, spleen size and age, and those with slow reduction of BCR-ABL1 transcripts in response to starting treatment are at increased risk of treatment failure [11,12,13].our study groups have previously demonstrated that the composition of the CD34þCD38À stem cell compartment at diagnosis, as assessed by multiparameter flow cytometry (MPFC) or stem and progenitor cell sorting followed by FISH, predicts for later response, and for hematologic toxicity during TKI treatment [14, 15]. We set out to assess whether analysis of the stem cell compartment at diagnosis and stem cell dynamics early after treatment initiation, such as the LSC reduction or, 4030 Clin Cancer Res; 22(16) August 15, 2016
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