HISTOLOGY AND HISTOPATHOLOGY

Cellular and Molecular Biology

 

Review

Effects of the tyrosine kinase inhibitor Imatinib mesylate (STI571) on bone marrow features in patients with chronic myelogenous leukemia

J. Thiele1, H.M. Kvasnicka1, A. Schmitt-Graeff2, S. Kriener3, K. Engels3, P. Staib4, M. Griesshammer5, C.F. Waller6, O.G. Ottmann7 and M.-L. Hansmann3

Institutes of Pathology, Universities of 1Cologne, 2Freiburg, 3Frankfurt, 4First Clinic of Medicine University of Cologne, 5Third Clinic of Medicine, University of Ulm, Germany, 6Department of Hematology/Oncology, University Medical Center, Freiburg and 7Department of Hematology, Center of Clinical Medicine, University of Frankfurt, Germany

Offprint requests to: Juergen Thiele, M.D., Institute of Pathology, University of Cologne, Joseph-Stelzmannstr. 9, D-50924 Cologne, Germany. Fax: +49-0221-4786360. e-mail: j.thiele@uni-koeln.de

Summary. Preliminary data are available about bone marrow (BM) changes in patients with chronic myeloid leukemia (CML) who received the molecularly targeted and highly effective tyrosine kinase inhibitor Imatinib mesylate (STI571). This review is focused on a systematic assessment of BM features detectable at different stages of CML (stable, accelerated, blastic) following long-term (more than 10 months) treatment. By applying enzyme- and immunohistochemistry including monoclonal antibodies visualizing proliferating cell nuclear antigen (PCNA) and apoptosis (anti-apostatin), a more elaborate insight into alterations affecting hematopoiesis and the stroma compartment was gained. In patients with stable-phase CML therapy resulted in a significant reduction in cellularity, neutrophil granulopoiesis and number of megakaryocytes, accompanied by a retrieval of erythroid precursors. In patients with Imatinib as the only treatment morphometric analysis of CD61+ megakaryopoiesis was in keeping with a significant decrease in maturation defects implying a lesser amount of atypical micromegakaryocytes almost consistent with normalization. Moreover, a reduction of the initially enhanced (CD34+) microvessel density was detectable associated with a decrease in luminal distension. Regression of marked to moderate myelofibrosis was recognizable in about 70% of patients especially in the accelerated and blastic phases. The amount of myeloblasts, CD34+ progenitor cells and lysozyme-expressing immature myelomonocytic cells declined with treatment, but recurred in about 19% of patients that developed a leukemic relapse after 21±6 months of therapy. Data on proliferative activity and apoptosis in general supported in vitro findings concerning the inhibitory effect of this agent on growth associated with a tendency for stimulated apoptosis, at least in responding patients. Histol Histopathol 19, 1277-1288 (2004)

Key words: Imatinib (STI571), neutrophil granulopoiesis, erythropoiesis, megakaryocytes, myelofibrosis, proliferation, apoptosis, bone marrow, CML

DOI: 10.14670/HH-19.1277