Imatinib Inhibits SCF-Induced Development Of Human Mast Cells In Vitro and Induces Profound and Selective Mast Cell Deficiency In Patients With Ph+ CML
Authors: Cerny-Reiterer Sabine , Rabenhorst Anja , Stefanzl Gabriele , Herndlhofer Susanne , Blatt Katharina , Hoermann Gregor , Muellauer Leonhard , Baumgartner Sigrid , Beham-Schmid Christine , Sperr Wolfgang R , Linkesch Werner , Mannhalter Christine , Arock Michel , Hartmann Karin , Valent Peter 
Published: October 2019

Abstract
Although mast cells (MC) play an important role as effector cells of allergic reactions and may contribute to vascular repair processes after a thromboembolic event, their physiological role in healthy tissues is currently unknown. In mice, several ´MC-deficiency models´ have been developed. In these models, MC-deficiency is usually triggered by a lack of KIT or lack of a functional KIT-ligand, stem cell factor (SCF). Currently, no comparable human model is available. We examined the in vitro and in vivo effects of the KIT-targeting drug imatinib on growth and differentiation of MC. Imatinib was found to inhibit SCF-induced development of human MC from cord blood-derived progenitors in an in vitro long-term culture assay (100 ng/ml SCF, day 28). The effects of imatinib on MC differentiation in this assay were dose-dependent (IC50: 0.01 µM). Correspondingly, efficacious long-term treatment of CML patients with imatinib (400 mg daily) resulted in a profound reduction of MC numbers. Whereas no substantial decrease in the numbers of MC was seen within the first year of treatment, the numbers of tryptase+ and KIT+ MC in the bone marrow (BM) decreased to less than 5% of pre-treatment values in 23 patients who were in continuous complete molecular response (CMR) for at least 2 years during imatinib therapy (numbers of tryptase+ BM cells: pre-treatment values: 21.1±13.7% of nucleated BM cells vs CMR-values in the same patients: 0.5±0.6% vs normal BM: 3.8±1.6%; p<0.001). Tryptase mRNA levels and KIT mRNA levels in the BM also decreased significantly during treatment with imatinib in these patients (p<0.01). Moreover, during treatment with imatinib, serum tryptase concentrations decreased to low or even undetectable levels (before therapy: 32.0±11.1 ng/ml vs CMR: 3.4±1.8 ng/ml, p<0.01). Other myeloid lineages in the BM, known to develop independently of KIT, were not affected by imatinib therapy. Remarkably, imatinib-induced MC deficiency was not accompanied by any specific symptoms or side effects (no increased rate of bacterial infections, thromboembolic events or secondary neoplastic lesions). In a next step, we examined MC numbers in C57BL/6J mice and cellular histamine levels in BALB/c mice treated with imatinib. In these experiments, we found that treatment with imatinib (60 mg/kg/day vs control saline by intraperitoneal=i.p. injection over 42 days; 4 mice per group) leads to a significant decrease in the numbers of MC (skin MC numbers per high power field in control mice: 36.7±10.1 versus imatinib-treated mice: 15.7±4.6, p<0.001). MC numbers and cellular histamine levels in peritoneal samples of BALB/c mice treated with imatinib (50 mg/kg/day i.p. vs control saline; 3 mice each) also decreased substantially during treatment with imatinib (histamine levels on day 24: imatinib: 9.2±1.4 ng/106 cells vs control: 75.7±2.1 ng/106cells, p<0.001). In conclusion, our data show that imatinib produces a profound MC deficiency in mice and men, without causing a particular clinical condition or syndrome. Based on these observations, we hypothesize that MC may be less relevant in physiologic processes and tissue homeostasis in healthy organs than has so far been assumed. Part of the work, including data on mast cells in BM sections, has been presented at EHA 2013. However, in our current ASH abstract, we have included additional data on mast cell numbers and histamine levels in 2 different mouse models. These mouse data have not been presented at EHA or any other congress before.

Disclosures:
Valent: Novartis: Consultancy, Honoraria, Research Funding.