Effects of imatinib on normal hematopoiesis and immune activation

The selective tyrosine kinase inhibitor imatinib (Glivec; Novartis International, Basel, Switzerland, http://www. glivec.com/content/home.jsp) is increasingly used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. In principle, the drug is well tolerated and clinical side effects are mostly moderate. However, it was shown that imatinib can affect the function of normal, nonmalignant cells, resulting in myelosuppression in treated patients. Recently, it has been demonstrated that imatinib might affect mobilization, proliferation, and differentiation of hematopoietic progenitor cells while leaving hematopoietic stem cells unaffected. Furthermore, in several in vitro studies and animal models, it was demonstrated that imatinib can affect the function and differentiation of antigen-presenting cells and inhibit the effector functions of T lymphocytes. Moreover, the induction of specific cytotoxic T cells seems to be impaired in chronic myeloid leukemia (CML) patients treated with imatinib compared with patients receiving interferon-alpha. This is of importance because some of the therapeutic effects in the treatment of patients with CML are mediated by the induction of leukemia-specific T-cell responses. Further studies investigating the effects of imatinib on normal hematopoiesis are of interest as they might lead to a better understanding of the clinically observed side effects and also might help identify new therapeutic applications of the drug, possibly in Ber-Abl-negative myeloproliferative disorders and potentially as an immunomodulatory agent.