Data from Leukemic Stem Cell Quantification in Newly Diagnosed Patients With Chronic Myeloid Leukemia Predicts Response to Nilotinib Therapy

Abstract

<div>Abstract<p><b>Purpose:</b> Leukemic stem cells (LSCs) may harbor important resistance to tyrosine kinase inhibitors in chronic myelogenous leukemia (CML). We identified Philadelphia chromosome (Ph)–positive CD34<sup>+</sup>CD38<sup>−</sup> bone marrow cells (here denoted LSCs) and addressed their response-predictive value in patients with CML (<i>n</i> = 48) subjected to nilotinib in the ENEST1st trial (NCT01061177).</p><p><b>Experimental design:</b> 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.</p><p><b>Results:</b> 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<sup>+</sup>CD38<sup>−</sup> 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.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 22(16); 4030–8. ©2016 AACR</i>.</p></div>