Long-term treatment with imatinib results in profound mast cell deficiency in Ph+ chronic myeloid leukemia

// Sabine Cerny-Reiterer 1,2 , Anja Rabenhorst 3 , Gabriele Stefanzl 2 , Susanne Herndlhofer 2 , Gregor Hoermann 4 , Leonhard Müllauer 5 , Sigrid Baumgartner 6 , Christine Beham-Schmid 7 , Wolfgang R. Sperr 1,2 , Christine Mannhalter 4 , Heinz Sill 8 , Werner Linkesch 8 , Michel Arock 9 , Karin Hartmann 3 and Peter Valent 1,2 1 Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria 2 Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria 3 Department of Dermatology, University of Cologne, Cologne, Germany 4 Department of Laboratory Medicine, Medical University of Vienna, Austria 5 Department of Pathology, Medical University of Vienna, Austria 6 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria 7 Institute of Pathology, Medical University of Graz, Austria 8 Department of Internal Medicine, Division of Hematology, Medical University of Graz, Austria 9 LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France Correspondence: Peter Valent, email: // Keywords : Mast Cells, KIT, Imatinib, Mast Cell Deficiency Received : October 31, 2014 Accepted : December 17, 2014 Published : December 26, 2014 Abstract Although mast cells (MC) play an important role in allergic reactions, their physiologic role remains unknown. In mice, several models of MC-deficiency have been developed. However, no comparable human model is available. We examined the in vitro - and in vivo effects of the KIT-targeting drug imatinib on growth and development of human MC. Imatinib was found to inhibit stem cell factor (SCF)-induced differentiation of MC in long-term suspension cultures (IC 50 : 0.01 µM). Correspondingly, long-term treatment of chronic myeloid leukemia (CML) patients with imatinib (400 mg/day) resulted in a marked decrease in MC. In patients with continuous complete molecular response during therapy, bone marrow MC decreased to less than 5% of pre-treatment values, and also serum tryptase concentrations decreased significantly (pre-treatment: 32.0±11.1 ng/ml; post-therapy: 3.4±1.8, p<0.01). Other myeloid lineages, known to develop independently of KIT, were not affected by imatinib-therapy. Imatinib also produced a substantial decrease in MC-development in mice. However, no clinical syndrome attributable to drug-induced MC-deficiency was recorded in our CML patients. Together, imatinib suppresses MC production in vitro and in vivo . However, drug-induced MC depletion is not accompanied by adverse clinical events, suggesting that MC are less relevant to homeostasis in healthy tissues than we assumed so far.