The Role of Farnesyl Transferase Inhibitors in the Treatment of Patients with Leukemia and Myelodysplastic Syndrome

Farnesyl transferase inhibitors (FTIs) inhibit farnesylation of various proteins playing a key role in cell growth and proliferation, including Ras, Rho, lamins, and centromere proteins. Several FTIs have demonstrated antitumor activity in preclinical models of several tumors, including hematologic malignancies. Nonpeptidomimetic FTIs, tipifarnib, lonafarnib, and BMS-214662 have demonstrated promising clinical activity along with acceptable toxicity profiles in the setting of leukemias and myelodysplastic syndrome (MDS). Tipifarnib and lonafarnib are in the most advanced stages of clinical development for the treatment of hematologic malignancies, including acute myeloid leukemia, chronic myeloid leukemia and MDS. Treatment with tipifarnib has been effective in the treatment of patients with acute myeloid leukemia and MDS, in the first-line and postremission (maintenance therapy) settings. Continuous administration of lonafarnib resulted in hematologic responses in patients with chronic myeloid leukemia and MDS with tolerable toxicities. Based on the results from various preliminary studies, FTIs are being pursued as important therapeutic options for the management of a variety of hematopoietic disorders.