Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients.

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.

Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy.

Tyrosine kinase inhibitors (TKIs) have potent effects on malignant cells, and they also target kinases in normal cells, which may have therapeutic implications. Using a collection of 55 leukemia patients treated with TKI therapy (chronic myeloid leukemia, n=47; acute lymphoblastic leukemia, n=8), we found that dasatinib, a second-generation broad-spectrum TKI, induced a rapid, dose-dependent and substantial mobilization of non-leukemic lymphocytes and monocytes in blood peaking 1-2 h after an oral intake and the blood counts closely mirrored drug plasma concentration. A preferential mobilization was observed for natural killer (NK), NK T, B and γδ+ T cells. Mobilization was coupled with a more effective transmigration of leukocytes through an endothelial cell layer and improved cytotoxicity of NK cells. Platelet numbers decreased markedly after the drug intake in a proportion of patients. Similar effects on blood cell dynamics and function were not observed with any other TKI (imatinib, nilotinib and bosutinib). Thus, dasatinib induces a unique, rapid mobilization and activation of cytotoxic, extravasation-competent lymphocytes, which may not only enhance antileukemia immune responses but can also be causally related to the side-effect profile of the drug (pleural effusions, thrombocytopenia).